It is well known that only a small subset of the human genome is considered druggable [1]}. Many proteins are deemed “undruggable” because there is no information on their ligand-binding properties or other interactions with small-molecule compounds (be they endogenous or exogenous ligands). Here, we built an “undruggable” human disease protein database by removing the druggable proteins in Pharos [2]} and Casas's druggable proteins [3]} from human disease associated genes [4]} and applied PortalCG to predict the probability for these “undruggable” proteins to bind to drug-like molecules. A total of 12,475 proteins were included in our disease-associated undruggable human protein list. These proteins were ranked according to their probability scores, and 267 of them have a false positive rate lower than 2.18e-05, as listed in the supplementary material Table S2. Table REF  shows the statistically significantly enriched functions of these top ranked proteins as determined by DAVID [5]}. The most enriched proteins are involved in alternative splicing of mRNA transcripts. Malfunctions in alternative splicing are linked to many diseases, including several cancers [6]}[7]} and Alzheimer's disease [8]}. However, pharmaceutical modulation of alternative splicing process is a challenging task. Identifying new drug targets and their lead compounds for targeting alternative splicing pathways may open new doors to developing novel therapeutics for complex diseases with few treatment options. Diseases associated with these 267 human proteins were also listed in Table REF . Since one protein is always related to multiple diseases, these diseases are ranked by the number of their associated proteins. Most of top ranked diseases are related with cancer development. 21 drugs that are approved or in clinical development are predicted to interact with these proteins as shown in Table S3. Several of these drugs are highly promiscuous. For example, AI-10-49, a molecule that disrupts protein-protein interaction between CBFb-SMMHC and tumor suppressor RUNX1, may bind to more than 60 other proteins. The off-target binding profile of these proteins may provide invaluable information on potential side effects and opportunities for drug repurposing and polypharmacology. The drug-target interaction network built for predicted positive proteins associated with Alzheimer's disease was shown in Figure REF . Functional enrichment, disease associations, and top ranked drugs for the undruggable proteins with well-studied biology (classified as Tbio in Pharos) and those excluding Tbio are list in Supplemental Table S4-S9.
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